Cirrhosis and its complication, hepatic encephalopathy (HE) are one of the leading causes of morbidity and mortality in the US. HE is associated with gut dysbiosis that is usually treated with antibiotics, prebiotics or probiotics. However, however HE often continues to recur and cause readmissions despite this standard of care. Multiple episodes of HE can result in cumulative irreversible brain injury. Therefore the prevention of recurrent HE is an important unmet need that requires translational intervention. Fecal microbiota transplant (FMT) is an effective translational approach for recurrent Clostridium difficile. Our preliminary data suggest that a one-time administration of an FMT-enema using a rationally-selected donor via Openbiome is safe in cirrhosis and recurrent HE. However, an upper GI route is preferable for patients and could favorably impact the small intestine, where translocation often occurs. The G3 FMT capsule by Openbiome acts on the small and large intestine and is available for C.difficile. We will use one donor specifically selected from the Openbiome pool whose microbial profile best fulfils the microbiota deficits related to beneficial bacteria in HE patients, utilizing a ?Precision Microbiome? approach. Ultimately the goal is to define oral FMT as a viable treatment approach for recurrent HE patients. Our hypothesis is that fecal transplants from a rationally derived donor delivered via capsules are safe and well tolerated in patients with cirrhosis and HE and are associated with significant improvement in gut microbiota composition, and mucosal defenses. The primary aim is: To evaluate the safety and tolerability of fecal transplant through oral capsules from a rationally derived donor in cirrhosis and HE from a liver disease and symptom standpoint. Secondary aims are (1) To define the changes in microbiota composition of the stool, duodenal and sigmoid colonic mucosa after oral FMT compared to pre-FMT baseline (2) To determine the effect of oral FMT on mucosal defenses by studying antimicrobial peptides, inflammatory cytokine expression and barrier protein expression compared to pre-FMT baseline. (3) To evaluate changes in systemic inflammatory cytokines and endotoxin after oral FMT compared to pre-FMT baseline. This will be an open-label trial of cirrhotic patients with HE carried out in collaboration CTSAs at Virginia Commonwealth University and the Medical College of Wisconsin along with Openbiome. Both CTSAs have expertise in the study of the gut-liver axis and mucosal defenses respectively. This research will form the platform for large, placebo-controlled, randomized trials for efficacy in this underserved population with scientific and clinical improvements in understanding of the gut-brain axis. This proposal is responsive to PA-16-343 by involving two separate CTSA hubs and performing ?Translational studies of the human microbiome? and ?Precision Medicine? as a method to advance knowledge within the CTSA consortium.